CN109705075B - Purification method of dapagliflozin - Google Patents
Purification method of dapagliflozin Download PDFInfo
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- CN109705075B CN109705075B CN201811528578.9A CN201811528578A CN109705075B CN 109705075 B CN109705075 B CN 109705075B CN 201811528578 A CN201811528578 A CN 201811528578A CN 109705075 B CN109705075 B CN 109705075B
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- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 78
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 78
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000000746 purification Methods 0.000 title claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000003756 stirring Methods 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 27
- 239000012074 organic phase Substances 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 8
- 229960004063 propylene glycol Drugs 0.000 claims description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 abstract description 21
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000007670 refining Methods 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 7
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- 229940083957 1,2-butanediol Drugs 0.000 description 2
- 229940035437 1,3-propanediol Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- BMRWNKZVCUKKSR-UHFFFAOYSA-N butane-1,2-diol Chemical compound CCC(O)CO BMRWNKZVCUKKSR-UHFFFAOYSA-N 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 1
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- -1 methyl tert-butyl Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a purification method of dapagliflozin, which comprises the following steps: 1) Dissolving the crude dapagliflozin product in an organic solvent immiscible with water, adding a polar reagent which is easy to form hydrogen bonds with hydroxyl, stirring and crystallizing to obtain a solid; 2) Adding the solid into an organic solvent which is not mutually soluble with water, adding a proper amount of water, stirring, dissolving the solid, dissolving a polar reagent in the water, standing, separating liquid, and concentrating an organic phase to obtain a refined dapagliflozin product; the method can effectively remove impurities in dapagliflozin, the purity of the refined dapagliflozin can reach more than 98.0%, and the purity of the refined dapagliflozin can reach more than 99.5% after multiple refining; the purification method of dapagliflozin provided by the invention can effectively remove impurities of dapagliflozin, is simple to operate, is safe and convenient, has low cost, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of compound purification methods, in particular to a dapagliflozin purification method.
Technical Field
The dapagliflozin is a sodium-glucose cotransporter 2 (SGLT 2) inhibitor which is jointly developed by Behcet-Meishiguibao and Aslicon and used for treating type 2 diabetes, and has a structural formula as follows:
in the preparation process of dapagliflozin, reagents with higher activity such as butyl lithium, triethylsilane and the like are used, and the prepared dapagliflozin has lower purity. Due to the low melting point of dapagliflozin, purification by recrystallization is difficult, and purification by column chromatography requires a large amount of solvent and column chromatography silica gel, which is expensive. The methods reported in patents CN101092409A, CN1896088A, CN101628905B, CN102627676B, CN100534997C, etc. change the melting point and solubility of the product by protecting groups for purification, and the specific methods are as follows:
according to the method, a tetrahydroxy acetylation product is prepared through acetylation reaction of a dapagliflozin crude product, then recrystallization is performed to obtain a tetraacetyl dapagliflozin product, and then hydrolysis is performed under an alkaline condition to obtain a dapagliflozin refined product. In addition, the above patent also reports another purification method, namely protection of acetyl protecting group in the previous step compound (O-methyl glucoside):
the method is adjusted compared with the method, protection is firstly carried out, then tetra-acetylated dapagliflozin is prepared by reduction, organic solvents such as methanol, ethanol, tetrahydrofuran, ethyl acetate and the like are used in both refining methods, and chemical reagents such as acetic anhydride, diisopropylethylamine, lithium hydroxide, N-dimethyl pyridine and the like are used in both refining methods. The purification method uses methods such as protecting group adding, refining and purifying, protecting group removing and the like, has longer route, higher cost and lower yield, and the yield is less than 50 percent through multi-step reaction.
Disclosure of Invention
Aiming at the problems, the invention provides a novel dapagliflozin purification method which is safe, environment-friendly and economic; the production cost is reduced, the method is suitable for large-scale production, and the method is realized by the following technical scheme:
a purification method of dapagliflozin comprises the following specific steps:
1) Dissolving the dapagliflozin crude product in an organic solvent A immiscible with water, adding a polar reagent which is easy to form hydrogen bonds with hydroxyl, crystallizing the dapagliflozin from the organic solvent A, and filtering to obtain a solid; impurities in the crude dapagliflozin product are difficult to crystallize and remain in the organic solvent, so that the aim of separating the dapagliflozin product from the impurities is fulfilled;
2) Adding the solid obtained in the step 1) into an organic solvent B immiscible with water, adding a proper amount of water, stirring, dissolving the solid, dissolving a polar reagent in the water, standing, separating liquid, transferring the organic phase into a single-port round glass reaction bottle, concentrating by using a rotary evaporator, and evaporating the organic phase to remove the solvent to obtain the purified dapagliflozin, wherein the purity of the purified dapagliflozin is more than 98.0%.
In the invention, the crude dapagliflozin is obtained by reducing O-methyl glucoside through triethylsilane and boron trifluoride diethyl etherate, and the specific preparation method refers to Chinese patent CN101628905B. Crude dapagliflozin is also commercially available.
Further, in the purification method of dapagliflozin, the water-immiscible organic solvent A used in the step 1) includes, but is not limited to: toluene, ethyl acetate, isopropyl acetate, methylene chloride, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane, heptane and the like, which are water-immiscible solvents. The dapagliflozin can be dissolved in the organic solvent A, and after the polar reagent is added, the dapagliflozin is crystallized from the solvent A, so that the aim of separating the dapagliflozin and impurities is fulfilled.
Further, in the purification method of dapagliflozin, the volume-to-mass ratio of the organic solvent A used in the step 1) to the crude dapagliflozin is 5/1-20/1 (ml/g, solvent volume unit ml, crude dapagliflozin mass unit g), and preferably 8/1-12/1.
Further, in the purification method of dapagliflozin of the present invention, the polar reagent which is easy to form hydrogen bond with hydroxyl used in step 1) includes but is not limited to: monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 2-butanol which are soluble in water; or 1, 2-ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol and the like can be dissolved in water; or trihydric alcohols such as glycerin which can be dissolved in water; the equivalent ratio of these polar reagents to the crude dapagliflozin is between 0.9/1 and 5/1, preferably between 1.0/1 and 2.0/1.
Further, in the purification method of dapagliflozin, the stirring crystallization temperature in the step 1) is not more than 30 ℃, the preferred temperature range is-10 ℃, the stirring crystallization time is not less than 2 hours, and the stirring speed is about 100rmb/min.
Further, in the purification method of dapagliflozin, the organic solvent B immiscible with water used in the step 2) includes, but is not limited to: toluene, ethyl acetate, isopropyl acetate, methylene chloride, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane, heptane and the like, which are water-immiscible solvents.
Further, in the purification method of dapagliflozin of the present invention, the volume-to-mass ratio of the organic solvent B used in step 2) to the solid obtained in step 1) (unit: ml/g) is between 5/1 and 20/1.
Further, in the purification method of dapagliflozin of the present invention, the volume ratio of water to the organic solvent B used in step 2) (unit: ml/ml) is between 2/1 and 0.3/1. Dissolving the crystallized solid in the step 1) in a mixed solvent of a solvent B and water, dissolving dapagliflozin in an organic solvent B, separating the dapagliflozin and a polar reagent in water, and thus preparing a dapagliflozin sample with higher purity.
Further, the purification method of dapagliflozin of the invention further comprises dissolving the purified dapagliflozin obtained in step 2) in the organic solvent A again, and repeating the steps 1) -2) to obtain the repurified dapagliflozin.
The purification method of the invention relates to the following chemical reaction:
compared with the prior art, the method has obvious advantages compared with the reported method.
(1) The purification process does not adopt the routes of protecting group addition, recrystallization and protecting group removal, and the reaction steps are shorter.
(2) A large amount of organic solvents and reagents are not used in the process, and the method is safe and environment-friendly. The used solvent is an organic solvent which is not dissolved in water, can be repeatedly used through post treatment, and has good water solubility, high safety and low toxicity.
(3) High yield, low cost, convenient operation and suitability for large-scale production.
Drawings
FIG. 1 is an H-NMR spectrum of a purified dapagliflozin product prepared in inventive example 1.
FIG. 2 is a C-NMR spectrum of a purified dapagliflozin product prepared in inventive example 1.
FIG. 3 is an IR spectrum of a purified dapagliflozin product prepared in inventive example 1.
FIG. 4 is an Ms spectrum of dapagliflozin purified product prepared in inventive example 1.
Detailed Description
The purpose and effects of the present invention will be fully understood from the detailed description given below.
In the examples, the crude dapagliflozin is obtained by reducing O-methyl glucoside through triethylsilane and boron trifluoride diethyl etherate reagent; o-methyl glucoside is purchased from a company and has a purity of more than 90.0% (area normalization); specific preparation method reference CN101628905B.
Example 1
Adding 120ml of ethyl acetate into a 250ml glass flask, adding 10.0g (0.0245 mol) of dapagliflozin crude product (purity is 75%), stirring for dissolving, adding 1.86g (0.0245 mol) of 1, 2-propylene glycol, stirring for 30min at 20 ℃, separating out a solid, continuing stirring for 3h, performing suction filtration, adding the obtained filter cake into a mixed solvent of 100ml of ethyl acetate and 50ml of purified water, stirring, gradually dissolving the solid, separating the liquid, washing the organic phase twice with purified water, washing the organic phase with 30ml of purified water each time, concentrating the organic phase by a rotary evaporator at 45 ℃ until no liquid is dripped out basically, and obtaining 6.30g of dapagliflozin refined product according to the formula: yield = dapagliflozin refined product quality/dapagliflozin crude product quality (the same in the following examples); the yield of dapagliflozin of the embodiment is 63.0 percent, and the purity is 98.42 percent. The purified product has less impurity signals in H-NMR and C-NMR spectra, and the sample has higher purity.
The purity was measured by HPLC using an inert sil ODS-SP 5um 4.6X 250mm column with a flow rate of 1.0ml/min, at 220nm, using methanol-water (75) as the mobile phase and area normalization.
Example 2
120ml of ethyl acetate is added into a 250ml glass flask, 10.0g (0.0245 mol) of dapagliflozin crude product (purity is 75%) is added, stirring is carried out to dissolve, 1.86g (0.0245 mol) of 1, 2-propylene glycol and 0.44g (0.0245 mol) of purified water are added, stirring is carried out for 20min under ice bath condition, solid is separated out, stirring is carried out for 3h continuously, suction filtration is carried out, the obtained filter cake is added into a mixed solvent of 100ml of ethyl acetate and 50ml of purified water, stirring is carried out, the solid is gradually dissolved, liquid separation is carried out, an organic phase is washed twice by purified water, 30ml of each time, the organic phase is concentrated to be dry, 7.23g of dapagliflozin primary refined product is obtained, yield is 72.3%, and purity is 98.36%.
The refined dapagliflozin product is refined by the same method, so that the purity is further improved.
Adding 120ml of ethyl acetate and 7.23g (0.0177 mol) of the once refined dapagliflozin into a 250ml glass flask, stirring and dissolving, adding 1.41g (0.019mol, 1.05eq) of 1, 2-propylene glycol, stirring for 20min under ice bath conditions, separating out solids, continuing stirring for 3h, performing suction filtration, adding the obtained filter cake into a mixed solvent of 100ml of ethyl acetate and 50ml of purified water, stirring, gradually dissolving the solids, separating, washing an organic phase with purified water twice, 30ml each time, concentrating the organic phase to be dry, and obtaining 6.48g of the once purified dapagliflozin, wherein the yield is 64.8 percent, and the purity is 99.84 percent.
Example 3
Adding 240ml of methyl tert-butyl ether and 30.2g (0.0739 mol) of dapagliflozin crude product (75%) into a 500ml glass flask, stirring for dissolving, adding 6.18g (0.0812mol, 1.1eq) of 1, 3-propylene glycol, then adding 1.46g (0.0812mol, 1.1eq) of purified water, stirring for 10 minutes at 5 ℃, separating out a solid, continuing stirring for 2 hours, performing suction filtration, adding the obtained solid into a mixed solvent of 300ml of isopropyl acetate and 100ml of purified water, dissolving the solid, standing and separating; the organic phase was washed with 100ml of water 2 times, and the organic phase was concentrated to give 22.10g of dapagliflozin refined product, with a yield of 73.2% and a purity of 98.48%.
Example 4
Adding 100ml isopropyl acetate into a 250ml reaction bottle, adding 10.0g (0.0245 mol) of the dapagliflozin crude product (purity 75%), stirring for dissolving, adding 1.76g (0.0294mol, 1.2eq) of 1-propanol, stirring for 1h at 10 ℃, continuously stirring for 5h after solid is separated out, performing suction filtration, adding the obtained solid into a mixed solvent of 80ml methyl tert-butyl and 40ml purified water, stirring, dissolving the solid, washing an organic phase for 2 times with water, 40ml each time, and concentrating the organic phase to obtain 6.12g of the dapagliflozin refined product, wherein the yield is 61.2%, and the purity is 98.14%.
Example 5
100ml of cyclohexane is added into a 250ml reaction bottle, 10.4g (0.0254 mol) of the crude dapagliflozin product (purity is 75%) is added, the mixture is stirred and dissolved, 1.68g (0.0280mol, 1.1eq) of 2-propanol is added, the mixture is stirred for 1h at 10 ℃, the solid is separated out, the stirring is continued for 5h, the suction filtration is carried out, the obtained solid is added into a mixed solvent of 80ml of n-heptane and 40ml of purified water, the stirring is carried out, the solid is dissolved, an organic phase is washed by water for 2 times, 40ml each time, and the organic phase is concentrated, so that 6.04g of the refined dapagliflozin product is obtained, the yield is 58.1%, and the purity is 98.25%.
In specific implementation, the organic solvent A can be any one or more of toluene, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane and heptane; the organic solvent B comprises: any one or more of toluene, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane and heptane; the organic solvent a and the organic solvent B may be the same reagent or different reagents.
The polar agent may be selected from: monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 2-butanol which are soluble in water; or 1, 2-ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, and the like, can be dissolved in water with a glycol; or trihydric alcohols such as glycerin which can be dissolved in water, can achieve the object of the present invention.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The above-mentioned embodiments, objects, technical solutions and advantages of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only examples of the present invention, and should not be construed as limiting the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A purification method of dapagliflozin is characterized by comprising the following specific steps:
1) Dissolving the dapagliflozin crude product in ethyl acetate, adding 1, 2-propylene glycol, stirring for crystallization, and filtering to obtain a solid;
the stirring crystallization temperature is not more than 30 ℃, and the stirring time is not less than 2h;
the volume mass ratio of the ethyl acetate to the dapagliflozin crude product is 8-12: 1, the volume-mass ratio unit is ml/g;
the equivalent ratio of the 1, 2-propylene glycol to the dapagliflozin crude product is 1.0-2.0: 1;
the crude product of the gelliflozin is obtained by reducing O-methyl glucoside through triethylsilane and boron trifluoride diethyl etherate reagents;
2) Adding the solid obtained in the step 1) into ethyl acetate, adding water, stirring until the solid is dissolved, standing for liquid separation, and evaporating an organic phase to obtain purified dapagliflozin;
the volume ratio of the water to the ethyl acetate is 2-0.3: 1.
2. the purification method of dapagliflozin according to claim 1, characterized in that the volume-to-mass ratio of the ethyl acetate in step 2) to the solid obtained in step 1) is 5-20: 1, the volume-mass ratio unit is ml/g.
3. The purification method of dapagliflozin according to claim 1 or 2, characterized in that, step 2) is to re-dissolve the obtained purified dapagliflozin in ethyl acetate, repeating steps 1) -2), obtaining re-purified dapagliflozin.
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